title: Potent benzimidazolone-based CGRP receptor antagonists.
abstract: The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. cory_theberge@merck.com
authors.forename: Cory R
authors.initials: CR
authors.lastname: Theberge
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Halea A
authors.initials: HA
authors.lastname: Corcoran
authors.forename: John F
authors.initials: JF
authors.lastname: Fay
authors.forename: James C
authors.initials: JC
authors.lastname: Hershey
authors.forename: Victor K
authors.initials: VK
authors.lastname: Johnston
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Scott
authors.initials: S
authors.lastname: Mosser
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
authors.forename: C Blair
authors.initials: CB
authors.lastname: Zartman
authors.forename: Xu-Fang
authors.initials: XF
authors.lastname: Zhang
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D007189:Indans / Q000737:chemistry*; D008253:Macaca mulatta; D015394:Molecular Structure; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007189:Indans; D013141:Spiro Compounds; C014353:benzimidazolone